PROJECT SUMMARY/ABSTRACT The goal of this project is to investigate strategies that augment the acquisition and retrieval of extinction memory as a means to compete with and subsequently inhibit the reemergence of drug memory during periods of cocaine reexposure. We previously developed a novel animal model of cue exposure therapy for cocaine addiction treatment that incorporates drug memory retrieval methods with extinction training as a means to inhibit cocaine relapse. We found that adding a glycine transporter-1 (GlyT-1) inhibitor significantly enhanced the effectiveness with which cocaine-cue extinction training subsequently reduces reacquisition of cocaine self- administration in adult male rats and monkeys. In this project, we propose to extend our treatment model to include environmental enrichment (EE), a documented behavioral procedure that improves learning and memory in rat and man. Our work will focus on the introduction of limited (4hr) periods of EE scheduled in conjunction with weekly sessions of cocaine-cue extinction training, an approach that augmented the rate of extinction learning and reduced reacquisition of cocaine self-administration in preliminary studies. To implement a multi-modal approach for which sex as a biological variable will be monitored, we will examine the combined effects of EE and GlyT-1 inhibition with cocaine-cue extinction training in adult male and female rats (Aim 1). Synergy between these combined treatments for augmenting acquisition and retrieval of extinction memory to reduce cocaine relapse is hypothesized. To broaden the scope of our investigation, we will examine molecular changes in key brain regions that underlie the effects of EE and a GlyT-1 inhibitor. We will focus on receptors for glutamate (NMDAR; AMPAR) and brain derived neurotrophic factor (TrkB) as well as on two novel targets Nedd4 and USP46, as these influence the primary cellular means by which learning, memory and synaptic plasticity unfold. Our preliminary studies support an investigation of these targets, particularly in basolateral amygdala and ventromedial prefrontal cortex. We plan a dual approach in which expression, trafficking and ubiquination of relevant protein targets (Aim 2) as well as viral-mediated knockdown and overexpression of those targets (Aim 3) will be studied in male and female rats treated with EE and a GlyT-1 inhibitor combined with extinction training. An investigation into how these two strategies (EE and GlyT-1 inhibition) synergize in combination in rats could have considerable scientific and clinical significance. Results from these studies will help identify mechanisms that mediate behavioral improvements attained through our multi-modal treatment intervention. Identifying critical changes in these targets as a result of extinction training combined with EE and GlyT-1 inhibition may aid in the development of pharmacotherapies with novel mechanisms of action and in the discovery of unique behavioral therapies that enable therapeutically relevant synaptic plasticity that inhibits relapse to cocaine abuse in adult men and women.